Dinuclear and mononuclear metal(II) polypyridyl complexes against drug-sensitive and drug-resistant Plasmodium falciparum and their mode of action.

BACKGROUND: Malaria remains one of the most virulent and deadliest parasitic disease in the world, particularly in Africa and Southeast Asia. Widespread occurrence of artemisinin-resistant Plasmodium falciparum strains from the Greater Mekong Subregion is alarming. This hinders the national economies, as well as being a major drawback in the effective control and elimination of malaria worldwide. Clearly, an effective anti-malarial drug is urgently needed. METHODS: The dinuclear and mononuclear copper(II) and zinc(II) complexes were synthesized in ethanolic solution and characterized by various physical measurements (FTIR, CHN elemental analysis, solubility, ESI-MS, UV-Visible, conductivity and magnetic moment, and NMR). X-ray crystal structure of the dicopper(II) complex was determined. The in vitro haemolytic activities of these metal complexes were evaluated spectroscopically on B+ blood while the anti-malarial potency was performed in vitro on blood stage drug-sensitive Plasmodium falciparum 3D7 (Pf3D7) and artemisinin-resistant Plasmodium falciparum IPC5202 (Pf5202) with fluorescence dye. Mode of action of metal complexes were conducted to determine the formation of reactive oxygen species using PNDA and DCFH-DA dyes, JC-1 depolarization of mitochondrial membrane potential, malarial 20S proteasome inhibition with parasite lysate, and morphological studies using Giemsa and Hoechst stains. RESULTS: Copper(II) complexes showed anti-malarial potency against both Pf3D7 and Pf5202 in sub-micromolar to micromolar range. The zinc(II) complexes were effective against Pf3D7 with excellent therapeutic index but encountered total resistance against Pf5202. Among the four, the dinuclear copper(II) complex was the most potent against both strains. The zinc(II) complexes caused no haemolysis of RBC while copper(II) complexes induced increased haemolysis with increasing concentration. Further mechanistic studies of both copper(II) complexes on both Pf3D7 and Pf5202 strains showed induction of ROS, 20S malarial proteasome inhibition, loss of mitochondrial membrane potential and morphological features indicative of apoptosis. CONCLUSION: The dinuclear [Cu(phen)-4,4'-bipy-Cu(phen)](NO3)4 is highly potent and can overcome the total drug-resistance of Pf5202 towards chloroquine and artemisinin. The other three copper(II) and zinc(II) complexes were only effective towards the drug-sensitive Pf3D7, with the latter causing no haemolysis of RBC. Their mode of action involves multiple targets.

Interaction of DNA with Simple and Mixed Ligand Copper(II) Complexes of 1,10-Phenanthrolines as Studied by DNA-Fiber EPR Spectroscopy.

The interaction of simple and ternary Cu(II) complexes of 1,10-phenanthrolines with DNA has been studied extensively because of their various interesting and important functions such as DNA cleavage activity, cytotoxicity towards cancer cells, and DNA based asymmetric catalysis. Such functions are closely related to the DNA binding modes of the complexes such as intercalation, groove binding, and electrostatic surface binding. A variety of spectroscopic methods have been used to study the DNA binding mode of the Cu(II) complexes. Of all these methods, DNA-fiber electron paramagnetic resonance (EPR) spectroscopy affords unique information on the DNA binding structures of the complexes. In this review we summarize the results of our DNA-fiber EPR studies on the DNA binding structure of the complexes and discuss them together with the data accumulated by using other measurements.

DNA molecular recognition and cellular selectivity of anticancer metal(II) complexes of ethylenediaminediacetate and phenanthroline: multiple targets.

By inhibiting only two or three of 12 restriction enzymes, the series of [M(phen)(edda)] complexes [M(II) is Cu, Co, Zn; phen is 1,10-phenanthroline; edda is N,N'-ethylenediaminediacetate] exhibit DNA binding specificity. The Cu(II) and Zn(II) complexes could differentiate the palindromic sequences 5'-CATATG-3' and 5'-GTATAC-3', whereas the Co(II) analogue could not. This and other differences in their biological properties may arise from distinct differences in their octahedral structures. The complexes could inhibit topoisomerase I, stabilize or destabilize G-quadruplex, and lower the mitochondrial membrane potential of MCF7 breast cells. The pronounced stabilization of G-quadruplex by the Zn(II) complex may account for the additional ability of only the Zn(II) complex to induce cell cycle arrest in S phase. On the basis of the known action of anticancer compounds against the above-mentioned individual targets, we suggest the mode of action of the present complexes could involve multiple targets. Cytotoxicity studies with MCF10A and cisplatin-resistant MCF7 suggest that these complexes exhibit selectivity towards breast cancer cells over normal ones.

[Zn(phen)(O,N,O)(H2O)] and [Zn(phen)(O,N)(H2O)] with O,N,O is 2,6-dipicolinate and N,O is L-threoninate: synthesis, characterization, and biomedical properties.

Two ternary Zn(II) complexes, with 1,10-phenanthroline (phen) as the main ligand and a carboxylate-containing ligand [dipicolinate (dipico) or L-threoninate (L-Thr)] as the subsidiary ligand, were prepared and characterized by elemental analysis, Fourier transform IR, UV, and fluorescence spectroscopy, X-ray diffraction, molar conductivity, and electrospray ionization mass spectrometry. X-ray structure analysis shows that both [Zn(phen)(dipico)(H(2)O)]·H(2)O (1) and [Zn(phen)(L-Thr)(H(2)O)Cl]·2H(2)O (2) have octahedral geometry about the Zn(II) atom. Both complexes can inhibit topoisomerase I, and have better anticancer activity than cisplatin against nasopharyngeal cancer cell lines, HK1 and HONE-1, with concentrations causing 50 % inhibition of cell proliferation (IC(50)) in the low micromolar range. Complex 2 has the highest therapeutic index for HK1. Both Zn(II) complexes can induce cell death by apoptosis. Changing the subsidiary ligand in the Zn(II) complexes affects the UV-fluorescence spectral properties of the coordinated phen ligand, the binding affinity for some DNA sequences, nucleobase sequence-selective binding, the phase at which cell cycle progression was arrested for treated cancer cells, and their therapeutic index.

Biological and cytoselective anticancer properties of copper(II)-polypyridyl complexes modulated by auxiliary methylated glycine ligand.

A series of ternary copper(II)-1,10-phenanthroline complexes with glycine and methylated glycine derivatives, [Cu(phen)(aa)(H(2)O)]NO(3)·xH(2)O 1-4 (amino acid (aa): glycine (gly), 1; DL: -alanine (DL: -ala), 2; 2,2-dimethylglycine (C-dmg), 3; sarcosine (sar), 4), were synthesized and characterized by FTIR, elemental analysis, electrospray ionization-mass spectra (ESI-MS), UV-visible spectroscopy and molar conductivity measurement. The determined X-ray crystallographic structures of 2 and 3 show each to consist of distorted square pyramidal [Cu(phen)(aa)(H(2)O)](+) cation, a nitrate counter anion, and with or without lattice water, similar to previously reported structure of [Cu(phen)(gly)(H(2)O)]NO(3)·1½H(2)O. It is found that 1-4 exist as 1:1 electrolytes in aqueous solution, and the cationic copper(II) complexes are at least stable up to 24 h. Positive-ion ESI-MS spectra show existence of only undissociated [Cu(phen)(aa)](+) species. Electron paramagnetic resonance, gel electrophoresis, fluorescence quenching, and restriction enzyme inhibition assay were used to study the binding interaction, binding affinity and selectivity of these complexes for various types of B-form DNA duplexes and G-quadruplex. All complexes can bind selectively to DNA by intercalation and electrostatic forces, and inhibit topoisomerase I. The effect of the methyl substituents of the coordinated amino acid in the above complexes on these biological properties are presented and discussed. The IC(50) values (24 h) of 1-4 for nasopharyngeal cancer cell line HK1 are in the range 2.2-5.2 µM while the corresponding values for normal cell line NP69 are greater than 13.0 µM. All complexes, at 5 µM, induced 41-60 % apoptotic cell death in HK1 cells but no significant cell death in NP69 cells.

Synthesis and Characterization of the Nanogold-Bound Ternary Copper(II) Complex of Phenanthroline and Cysteine as Potential Anticancer Agents.

The aim of this study was to synthesize and characterize a nanogold-{[(Cu)(phen)(cys)(H2O)]NO3}n conjugate and to evaluate its antiproliferative property against the breast cancer cell line (MCF7) and normal cell line (MCF10A). Nanogold solution was prepared using the Turkevich method. In one approach, a ternary copper(II) complex of 1,10-phenanthroline with l-cysteine, [(Cu)(phen)(cys)(H2O)]NO3, was first prepared and then tethered with the gold nanoparticles. In another approach, gold nanoparticles were reacted with l-cysteine, copper(II) nitrate, and 1,10-phenanthroline subsequently. The synthesized [(Cu)(phen)(cys)(H2O)]NO3 complex was characterized by Fourier transform infrared (FTIR) and electrospray ionization mass spectrometry techniques, which showed that l-cysteine was bound to the copper through carboxylic and amino groups, with the thiol moiety remaining free. The free thiol group was bound to the nanogold surface to form the nanogold-{[(Cu)(phen)(cys)(H2O)]NO3}n conjugate, as evidenced by the increase in the surface plasmon absorption band in ultraviolet-visible and the absence of a thiol peak in FTIR of the nanogold-copper complex conjugate. The anticancer activity of the nanogold-copper complex conjugate and the free copper complex against a breast cancer cell line (MCF7) and their toxicity on a normal cell line (MCF10A) were examined using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy phenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. Results suggested that the nanogold-{[(Cu)(phen)(cys)(H2O)]NO3}n conjugate demonstrates a selective antiproliferative and proapoptotic effect on the breast cancer cells, confirming the potential of the nanogold-copper complex conjugate as an anticancer agent.

Synthesis, characterization and multiple targeting with selectivity: Anticancer property of ternary metal phenanthroline-maltol complexes.

The cobalt(II), copper(II) and zinc(II) complexes of 1,10-phenanthroline (phen) and maltol (mal) (complexes 1, 2, 3 respectively) were prepared from their respective metal(II) chlorides and were characterized by FT-IR, elemental analysis, UV spectroscopy, molar conductivity, p-nitrosodimethylaniline assay and mass spectrometry. The X-ray structure of a single crystal of the zinc(II) analogue reveals a square pyramidal structure with distinctly shorter apical chloride bond. All complexes were evaluated for their anticancer property on breast cancer cell lines MCF-7 and MDA-MB-231, and normal cell line MCF-10A, using (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and morphological studies. Complex 2 was most potent for 24, 48 and 72 h treatment of cancer cells but it was not selective towards cancer over normal cells. The mechanistic studies of the cobalt(II) complex 1 involved apoptosis assay, cell cycle analysis, dichloro-dihydro-fluorescein diacetate assay, intracellular reactive oxygen species assay and proteasome inhibition assay. Complex 1 induced low apoptosis, generated low level of ROS and did not inhibit proteasome in normal cells. The study of the DNA binding and nucleolytic properties of complexes 1-3 in the absence or presence of H2O2 or sodium ascorbate revealed that only complex 1 was not nucleolytic.

Crystal structure, DNA binding studies, nucleolytic property and topoisomerase I inhibition of zinc complex with 1,10-phenanthroline and 3-methyl-picolinic acid.

Crystal structure analysis of the zinc complex establishes it as a distorted octahedral complex, bis(3-methylpicolinato-kappa(2) N,O)(2)(1,10-phenanthroline-kappa(2) N,N)-zinc(II) pentahydrate, [Zn(3-Me-pic)(2)(phen)]x5H(2)O. The trans-configuration of carbonyl oxygen atoms of the carboxylate moieties and orientation of the two planar picolinate ligands above and before the phen ligand plane seems to confer DNA sequence recognition to the complex. It cannot cleave DNA under hydrolytic condition but can slightly be activated by hydrogen peroxide or sodium ascorbate. Circular Dichroism and Fluorescence spectroscopic analysis of its interaction with various duplex polynucleotides reveals its binding mode as mainly intercalation. It shows distinct DNA sequence binding selectivity and the order of decreasing selectivity is ATAT > AATT > CGCG. Docking studies lead to the same conclusion on this sequence selectivity. It binds strongly with G-quadruplex with human tolemeric sequence 5'-AG(3)(T(2)AG(3))(3)-3', can inhibit topoisomerase I efficiently and is cytotoxic against MCF-7 cell line.

Bis(µ-5-hydr-oxy-2-{[2-(N-phenyl-thio-carbamo-yl)hydrazin-1-yl-idene]meth-yl}phenolato)bis[chloridozinc(II)] N,N-dimethyl-formamide tetra-solvate.

In the dinuclear title compound, [Zn(2)(C(14)H(12)N(3)O(2)S)(2)Cl(2)]·4C(3)H(7)NO, the two monodeprotonated Schiff base ligands N,O,S:O-chelate to Zn atoms. The formally negatively charged O atom involved in chelation also serves as a bridge. The O, O', N and S atoms comprise a square, and the Cl atom the apex of a square pyramid surrounding each metal atom. The solvate dimethyl-formamide mol-ecules, one of which is disordered over two positions in a 3:1 ratio, are hydrogen bonded to the dinuclear mol-ecule.

Diaqua-(1,4,8,11-tetra-aza-cyclo-tetra-deca-ne)nickel(II) fumarate tetra-hydrate.

The asymmetric unit of the title complex salt, [Ni(C(10)H(24)N(4))(H(2)O)(2)](C(4)H(2)O(4))·4H(2)O, comprises half of a nickel(II) complex dication, half of a fumarate dianion and two water mol-ecules. Both the Ni(II) cation and fumarate anion lie on a crystallographic inversion center. The Ni(II) ion in the cyclam complex is six-coordinated within a distorted N(4)O(2) octa-hedral geometry, with the four cyclam N atoms in the equatorial plane and the two water mol-ecules in apical positions. The six-membered metalla ring adopts a chair conformation, whereas the five-membered ring exists in a twisted form. In the crystal packing, inter-molecular O-H⋯O hydrogen bonds between the water molecules and the carboxyl groups of the fumarate anions lead to the formation of layers with R(4) (2)(8) ring motifs. Ni(II) complex cations are sandwiched between two such layers, being held in place by O-H⋯O, N-H⋯O and C-H⋯O hydrogen bonds, consolidating a three-dimensional network.

Current progress in antimalarial pharmacotherapy and multi-target drug discovery.

Discovery and development of antimalarial drugs have long been dominated by single-target therapy. Continuous effort has been made to explore and identify different targets in malaria parasite crucial for the malaria treatment. The single-target drug therapy was initially successful, but it was later supplanted by combination therapy with multiple drugs to overcome drug resistance. Emergence of resistant strains even against the combination therapy has warranted a review of current antimalarial pharmacotherapy. This has led to the development of the new concept of covalent biotherapy, in which two or more pharmacophores are chemically bound to produce hybrid antimalarial drugs with multi-target functionalities. Herein, the review initially details the current pharmacotherapy for malaria as well as the conventional and novel targets of importance identified in the malaria parasite. Then, the rationale of multi-targeted therapy for malaria, approaches taken to develop the multi-target antimalarial hybrids, and the examples of hybrid molecules are comprehensively enumerated and discussed.

Chlorido(pentane-2,4-dionato-κO,O')(1,10-phenanthroline-κN,N')copper(II).

The Cu(II) atom in the title compound, [Cu(C(5)H(7)O(2))Cl(C(12)H(8)N(2))], shows a distorted square-planar coordination; the chelating N and O atoms occupy the basal sites and the Cl atom the apical site. The square-pyramidal character along the Berry D(3h)-C(4v) pseudorotation pathway is 92%.

(2,2'-Bipyridine-κN,N')(4-hydr-oxy-2-oxidobenzaldehyde thio-semicar-ba-zon-ato-κO,N,S)zinc(II).

The Zn(II) atom in the title compound, [Zn(C(8)H(7)N(3)O(2)S)(C(10)H(8)N(2))], is N,N'-chelated by the heterocycle and N,O,S-chelated by the doubly deprotonated Schiff base ligand in a distorted square-pyramidal environment. O-H⋯O and N-H⋯N hydrogen bonds link adjacent mol-ecules into a layer structure.

[1-(4-Hydr-oxy-2-oxidobenzyl-idene)-4-phenyl-thio-semicarbazonato-κN,O,S](1,10-phenanthroline-κN,N')zinc(II)-4,4'-bipyridine (2/1).

The Zn(II) atom in the title compound, [Zn(C(14)H(11)N(3)O(2)S)(C(12)H(8)N(2))]·0.5C(10)H(8)N(2), is N,N'-chelated by the N-heterocycle and N,O,S-chelated by the deprotonated Schiff base in a square-pyramidal environment. The hydr-oxy group of the Schiff base is a hydrogen-bond donor to 4,4'-bipyridine, which is located about a center of inversion, resulting in the formation of a supra-molecular trimeric unit.

Bis(acetone 4-phenyl-thio-semi-carbazonato-κN,S)zinc(II).

The Zn(II) atom in the title compound, [Zn(C(10)H(12)N(3)S)(2)], is N,S-chelated by the deprotonated Schiff base in a tetra-hedral environment. The metal atom lies on a twofold rotation axis that relates one anion to the other. The amino H atom forms an intermolecular N-H⋯π inter-action to an aromatic ring.

Bis(µ-4-hydr-oxy-2-oxidobenzaldehyde 4-ethyl-thio-semicarbazone)-κO,N,S:O;κO:O,N,S-bis-[chloridozinc(II)] dimethyl sulfoxide tris-olvate.

The two Zn(II) atoms in the title compound, [Zn(2)(C(10)H(12)N(3)O(2)S)(2)Cl(2)]·3C(2)H(6)OS, are each N,O,S-chelated by a mono-deprotonated Schiff base ligand. The Zn atoms are bridged through the phenolate O atom, leading to a central Zn(2)O(2) core. Each Zn atom has a Cl atom in the apical position of a distorted square-pyramidal environment. Hydr-oxy-DMSO (DMSO is dimethyl sulfoxide) O-H⋯O and amide-DMSO N-H⋯O hydrogen bonds link the components of the crystal structure. Two of the DMSO mol-ecules are partially disordered, with each modelled over two sites of equal weight.

The potential therapeutic actions of melatonin in colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer and lethal disease worldwide. Melatonin, an indoleamine produced in pineal gland, shows anticancer effects on a variety of cancers, especially CRC. After clarifying the pathophysiology of CRC, the association of circadian rhythm with CRC, and the relationship between shift work and the incidence of CRC is reviewed. Next, we review the role of melatonin receptors in CRC and the relationship between inflammation and CRC. Also included is a discussion of the mechanism of gene regulation, control of cell proliferation, apoptosis, autophagy, antiangiogenesis and immunomodulation in CRC by melatonin. A review of the drug synergy of melatonin with other anticancer drugs suggests its usefulness in combination therapy. In summary, the information compiled may serve as comprehensive reference for the various mechanisms of action of melatonin against CRC, and as a guide for the design of future experimental research and for advancing melatonin as a therapeutic agent for CRC.

Enantiomeric pairs of ternary copper(ii) complexes and their aldol-type condensation products: synthesis, characterization, and anticancer and epigenetic properties.

Chiral enantiomers [Cu(phen)(l-ser)(H2O)]NO31 and [Cu(phen)(d-ser)(H2O)]NO32 (ser = serinato) underwent aldol-type condensation with formaldehyde, with retention of chirality, to yield their respective enantiomeric ternary copper(ii) complexes, viz. l- and d-[Cu(phen)(OCA)(H2O)]NO3·xH2O (3 and 4; phen = 1,10-phenanthroline; OCA = oxazolidine-4-carboxylate; x = 1/2, 0-2) respectively. These chiral complexes were characterized by FTIR, elemental analysis, circular dichroism, UV-visible spectroscopy, fluorescence spectroscopy (FL), molar conductivity measurement, ESI-MS and X-ray crystallography. The crystal structures of 1 and 3 showed both the cationic complexes to have a square pyramidal geometry. These complexes were about nine fold more potent than cisplatin against metastatic MDA-MB-231 breast cancer cells, inducing apoptotic cell death via ROS generation and a massive drop in mitochondrial membrane potential. The results of monitoring EZH1, EZH2 and H3K27me3 revealed that the mode of action of 1-4 also involved the downregulation of EZH2 and it seemed to be independent of the H3K27me3 status.

µ-Nitrilo-triacetato-tris(1,10-phenanthroline)dizinc(II) nitrate hexa-hydrate.

The nitrilo-triacetate trianion in the title compound, [Zn(2)(C(6)H(6)NO(6))(C(12)H(8)N(2))(3)]NO(3)·6H(2)O, is engaged in N,O,O',O"-chelation to the phenanthroline-chelated Zn(II) unit, giving a distorted octa-hedral geometry for the metal atom. One of the three O atoms of the trianion that is engaged in chelation also binds to the bis-(phenanthroline)-chelated Zn(II) unit, whose five-coordinate geometry is distorted owing to a long Zn⋯O inter-action [2.401 (2) Å]. The dinuclear cations, nitrate anions and uncoordinated water mol-ecules are linked into a three-dimensional network via O-H⋯O hydrogen bonds between water molecules and carboxylate O atoms.

Aqua-(imino-diacetato-κO,N,O')(1,10-phenanthroline-κN,N')cobalt(II) monohydrate.

The imino-diacetate dianion in the title compound, [Co(C(4)H(5)NO(4))(C(12)H(8)N(2))(H(2)O)]·H(2)O, chelates to the cobalt(II) atom, its N and two O atoms occupying the fac sites of the distorted octa-hedron around the metal atom. The metal atom is also chelated by the N-heterocycle. The dianion, and coordinated and uncoordinated water mol-ecules inter-act through hydrogen bonds, generating a layer motif. The crystal studied was a racemic twin with a 0.62 (2):0.38 (2) domain ratio.